Human papillomaviruses (HPVs) are associated with benign and malignant proliferative lesions of squamous epithelium. The host immune response to HPV infections is not well characterized, in part because HPV-encoded proteins to serve as antigen targets are difficult to obtain. HPVs infect exclusively human squamous epithelial cells, and generally do not replicate to high densities in naturally infected tissues. HPVs have not been successfully propagated in tissue culture cells, and humans are the only known animal host. As an alternative source of HPV-encoded proteins to serve as antigen in assays of immune reactivity, we have expressed DNA fragments from the open reading frames (ORFs) of cloned HPV6b, HPV16, and HPV18 DNAs in Escherichia coli be recombinant genetic techniques. These HPV types are of particular interest because they are associated with biologically distinct diseases of the female genital tract: HPV6b is most often found in common genital warts (condylomata acuminata), and HPV16 and HPV18 are frequently associated with uterine cervical dysplasia and cervical carcinoma. The HPV-encoded proteins will be used in immunological assays to address several issues: 1) to identify those HPV proteins which induce humoral and cellular immune responses in benign and malignant HPV diseases of the female genital tract, 2) to determine whether the reactivities to HPV6b, HPV 16, and HPV18 proteins are type-specific or cross-reactive, 3) to characterize the natural history of the immune responses in HPV-related diseases, and 40 to determine whether immune reactivities are modified by therapeutic intervention. The locations of humoral and cellular immune epitopes will be mapped by using exonuclease III-deleted fusion protein constructs and HPV-derived synthetic peptides. This information may be valuable in further characterizing the relationship of HPVs to benign and malignant diseases of the genital tract, in evaluating the effects of therapeutic interventions, and in developing HPV vaccines.